Severe Bone Research Articles

Home self-testing of complete blood counts in patients with breast cancer during chemotherapy: A proof-of-concept cohort study in e-oncology.

Before administration of myelosuppressive chemotherapy, complete blood counts (CBC) collected at the hospital/nursing stations are evaluated to avoid severe bone marrow suppression. This maintains disease fixation which often reduces their quality of life. This mixed-method study examined at home self-testing of CBC, the test quality, and the effects on patients' mental well-being. Patients with breast cancer receiving chemotherapy were recruited and trained to perform capillary finger prick CBC testing at home using the HemoScreen Point-of-Care instrument and to upload the test results to the hospital's IT system subsequently. A venous reference CBC sample was taken and tested at the hospital on the day of self-testing. Semi-structured interviews with open-ended components were performed to investigate the user experience and the impact of self-testing on the patients' everyday lives. Thirty-nine patients completed the self-testing education using the HemoScreen instrument. Eight patients withdrew, while the remaining 31 patients performed 161 home tests (2-11 tests per patient) over a 4-month period. The test results compared well with the venous reference CBCs except for platelet counts (correlation coefficient 0.26). Qualitative interviews with nine of the 31 patients emphasized that the patients were comfortable using the self-testing instrument and becoming an active partner in their own treatment. CBC self-testing at home produced clinically valid hemoglobin and white blood cell counts with the added benefit that the patients became active partners in their own treatment course, which was of great importance for the patients and increased their wellbeing.

Tenascin C Deletion Impairs Tendon Healing and Functional Recovery After Rotator Cuff Repair.

The biological factors that affect healing after rotator cuff repair (RCR) are not well understood. Genetic variants in the extracellular matrix protein Tenascin C (TNC) are associated with impaired tendon healing and it is expressed in rotator cuff tendon tissue after injury, suggesting it may have a role in the repair process. The purpose of the current study was to determine the role of TNC on tendon healing after RCR in a murine model. The supraspinatus tendon was transected and repaired on the left shoulder of Wild-Type (WT-RCR), Tenascin C null (Tnc --RCR) and Tnc heterozygous (Tnc +/--RCR) mice. Controls included the unoperated, contralateral shoulder of WT-RCR, Tnc - RCR, Tnc +/--RCR mice and unoperated shoulders from age and genotype matched controls. We performed histologic, activity testing, RNA-seq, and biomechanical analyses. At 8-weeks post-RCR, Tnc - and Tnc +/- mice had severe bone and tendon defects following rotator cuff repair. Tnc --RCR mice had reduced activity after rotator cuff repair including reduced wheel rotations, wheel duration, and wheel episode average velocity compared with WT-RCR. Loss of Tnc following RCR altered gene expression in the shoulder, including upregulation of sex hormone and WNT pathways and a downregulation of inflammation and cell cycle pathways. Tnc - mice had similar biomechanical properties after repair as WT. Further research is required to evaluate tissue specific alterations of Tnc, the interactions of Tnc and sex hormone and inflammation pathways as well as possible adjuvants to improve enthesis healing in the setting of reduced TNC function.

Mid-term Survivorship and Functional Outcomes of Metaphyseal Sleeves for Addressing Anderson Orthopaedic Research Institute (AORI) Type 2 and 3 Bone Defects in Revision Total Knee Arthroplasty.

Introduction Revision Total Knee Arthroplasty (RTKA) is a complex procedure challenged by significant bone loss, necessitating effective restoration techniques. This study investigates the clinical outcomes and complications of metaphyseal sleeves in RTKA with severe metaphyseal bone loss, aiming to evaluate their efficacy over a minimum four-year follow-up. Methods This was a retrospective observational study on 29 patients who underwent RTKA with Anderson Orthopaedic Research Institute (AORI) type II or III bone defects using porous coated tibial and/or femoral metaphyseal sleeves from December 2016 and January 2019. Data collection included demographic information, etiology for revision, and functional outcomes assessed by the Knee Society Score (KSS) and Oxford Knee Score (OKS). Statistical analysis and Kaplan-Meier survival analysis were performed. Results The cohort comprised patients with a mean age of 62.6 years (SD=7.8), predominantly female (N=21, 71.4%). The primary indication for RTKA was aseptic loosening (N=18, 62.1%) followed by Prosthetic Joint Infection (PJI). Significant improvements were noted in the range of motion. Both KSS (Pre-op:57.97 vs. Post-op:73.59) and OKS (Pre-op:15.86 vs. Post-op:30.66) showed highly significant improvement (p<0.0001). Radiographic assessments indicated stable component position and signs of osseous integration without any osteolysis. No sleeve-related complications were observed. Survival analysis demonstrated a high cumulative survival probability over the study period. Conclusion Metaphyseal sleeves offer a viable solution for managing severe bone loss in RTKA, providing stable fixation, restoring joint line kinematics, and facilitating stress distribution to the metaphyseal region. This study corroborates the effectiveness of metaphyseal sleeves in challenging revision scenarios, aligning with previous research.

Correction of osteopetrosis in the neonate oc/oc murine model after lentiviral vector gene therapy and non-genotoxic conditioning.

Autosomal recessive osteopetrosis (ARO) is a rare genetic disease, characterized by increased bone density due to defective osteoclast function. Most of the cases are due to TCIRG1 gene mutation, leading to severe bone phenotype and death in the first years of life. The standard therapy is the hematopoietic stem cell transplantation (HSCT), but its success is limited by several constraints. Conversely, gene therapy (GT) could minimize the immune-mediated complications of allogeneic HSCT and offer a prompt treatment to these patients. The Tcirg1-defective oc/oc mouse model displays a short lifespan and high bone density, closely mirroring the human condition. In this work, we exploited the oc/oc neonate mice to optimize the critical steps for a successful therapy. First, we showed that lentiviral vector GT can revert the osteopetrotic bone phenotype, allowing long-term survival and reducing extramedullary haematopoiesis. Then, we demonstrated that plerixafor-induced mobilization can further increase the high number of HSPCs circulating in peripheral blood, facilitating the collection of adequate numbers of cells for therapeutic purposes. Finally, pre-transplant non-genotoxic conditioning allowed the stable engraftment of HSPCs, albeit at lower level than conventional total body irradiation, and led to long-term survival and correction of bone phenotype, in the absence of acute toxicity. These results will pave the way to the implementation of an effective GT protocol, reducing the transplant-related complication risks in the very young and severely affected ARO patients.

Navigating the clinical landscape: Update on the diagnostic and prognostic biomarkers in multiple myeloma.

Multiple myeloma, a complex hematologic malignancy, has devastating consequences for patients, including dramatic bone loss, severe bone pain, and pathological fractures that markedly decrease the quality of life and impact the survival of affected patients. This necessitates a refined understanding of biomarkers for accurate diagnosis and prognosis of such severe malignancy. Therefore, this article comprehensively covers current research, elucidating the diverse spectrum of biomarkers employed in clinical settings. From traditional serum markers to advanced molecular profiling techniques, the review provides a thorough examination of their utility and limitations. Through this scoping review, emphasis is placed on the evolving landscape of personalized medicine, where biomarkers play a pivotal role in tailoring therapeutic strategies. The integration of genomic, proteomic, next generation sequencing and flow cytometric data further enriches the discussion, unravelling the molecular intricacies underlying disease progression. The updated criteria allow for the treatment of people who clearly would benefit from therapy and might live longer if treated before significant organ damage occurs. Navigating through the evolving diagnostic and prognostic paradigms in multiple myeloma, this article equips clinicians and researchers with crucial insights for optimizing patient care and advancing future therapeutic approaches.

A combination of osteosynthesis in proximal femur fracture and contralateral femoral neck local osteo-enhancement procedure (LOEP) in severe osteoporotic bone loss

Proximal femur fractures are among the main causes of mortality and morbidity worldwide in the elderly female population. Research efforts are currently focused on the development of a procedure that has immediate and long-term effectiveness, although pharmacological therapies are already capable of improving bone density and reducing the risk of fracture. A local bone enhancement procedure (LOEP) has been developed to facilitate bone augmentation. The procedure requires the preparation of an area of osteoporotic bone into which a triphasic, resorbable, calcium-based material is injected. Following the procedure, both the bone mineral density of the proximal femur and the bone resistance to compression and distraction forces acting on the femoral neck, which can cause fracture, are significantly improved. Ten women suffering from severe osteoporosis and intertrochanteric fracture underwent preliminary investigations after application of a local bone-strengthening procedure involving the use of AGN1 and nailing of the contralateral proximal femur. KEY WORDS: Proximal femur fracture, osteoporosis, local osteo-enhancement procedure (LOEP), proximal femoral nail (PFN).

TAXA DE FALHA DE PROTOCOLO UTILIZANDO A TÉCNICA ALL-ON-4: UMA REVISÃO NARRATIVA

Oral rehabilitation through dental implants is a fundamental solution for restoring the quality of life in edentulous patients and has been widely used due to its high success rates. The all-on-four concept combines two anterior axial implants and two posterior angled implants, making it a viable rehabilitation option for patients with severe bone loss, minimizing the complexity of the surgical procedure, and enabling immediate rehabilitation. Although it presents excellent success rates, it is important to understand the risk factors for implant survival failure. The aim of this work is to conduct a narrative review of the literature and, from it, analyze the failure rates of rehabilitations using the all-on-four protocol. The possible factors identified were gender, maxillary bone, smoking, presence of bruxism, systemic diseases, and previous periodontitis. The implant survival rate confirmed the high success rates of the technique, varying between 94% and 99%. Smoking was shown to be the main risk factor for failure, a variable present in all reviewed articles. The presence of bruxism also presented relevance, albeit more discreetly. The other factors did not show significant impact. It is concluded that there is a need for a greater number of randomized clinical trials with larger samples and long-term follow-up, as the current evidence is limited by the quality of available studies and the scarcity of data on longer clinical outcomes.

Horizontal Ridge Augmentation Using Sticky Bone with Platelet-Rich Fibrin (PRF) in Anterior Maxilla Clinical and Histologic Evidence: A Case Report

Alveolar ridge deficiency is an unavoidable sequela of tooth extraction and poses major clinical challenges when reconstruction is anticipated. Various surgical approaches have been proposed to address horizontal defects, with autogenous bone grafting considered the current benchmark. However, alternative methods, utilizing tissue engineering principles and bone substitutes, offer reduced patient morbidity. This report presents an alternative case of severe horizontal bone defect augmentation in the anterior maxilla using sticky bone in conjunction with platelet-rich fibrin (PRF), and a Ti-reinforced membrane. Histologic evidence of sticky, deproteinized bovine bone material (DBBM) mixed with PRF without the use of autogenous bone is reported.

Rotating-Hinge Total Knee Arthroplasty: Clinical and Radiographic Results from a Medium-Term, Multi-Center Study in a Latin American Population

Background: Hinged prostheses are a good choice in the setting of complex knee arthroplasty. Nevertheless, the results could be different in the Latin-American people. Methods: A retrospective follow-up was performed. Seventy-six patients underwent pTKA using hinged prosthesis from 2012 to 2017. Survival analysis was performed with the Kaplan-Meier method. Functional results were assessed using Oxford Knee Score (OKS), OKS-APQ (Activity and Participation Questionnaire) and KOOS-12. Radiologic assessment was performed at each follow-up. In all the surgeries the rotating-hinge prosthesis solved the cases of complex knee surgery. Results: Seventy-six patients underwent pTKA using hinged prosthesis from 2012 to 2017. Survival analysis was performed with the Kaplan-Meier method. Functional results were assessed using Oxford Knee Score (OKS), OKS-APQ (Activity and Participation Questionnaire) and KOOS-12. Radiologic assessment was performed at each follow-up. In all the surgeries the rotating-hinge prosthesis solved the cases of complex knee surgery. Hinge prostheses for complex knee arthroplasty in Latin-American people have a 10-year survivorship of 90.8% which is within the range of 51% to 92.5%, shown in a recent literature review of non-Latin American world population. Conclusions: Rotating Hinge prostheses are a good option for patients with major deformities, grade 3 ligament instability, neurological sequalae that compromises the knee joint and severe bone loss. The Latin-American population shows a similar behavior in terms of survivorship in comparison with the literature from the rest of the world. However, comparative studies with greater statistical power are needed to show more accurate conclusions. Level of Evidence: Level III

Advanced 3D printed bone scaffolds with sodium alginate/Tri-calcium phosphate/probiotic bacterial hydroxyapatite: Enhanced mechanical and biocompatible properties for bone tissue engineering

IntroductionThe increasing prevalence of severe bone diseases, such as osteoporosis and critical bone defects, necessitates the development of more effective bone substitutes. This study addresses this need by investigating 3D-printed bone scaffolds composed of sodium alginate and tricalcium phosphate, enhanced with three distinct types of hydroxyapatite (HA): bovine-derived HA, commercially available HA, and HA enriched with probiotic bacteria. We aim to evaluate the performance of these scaffolds in terms of mechanical strength, biocompatibility, and their ability to support bone regeneration. MethodsThe scaffolds were analyzed through various tests, including X-ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) to characterization. Scanning Electron Microscopy (SEM) was used to examine pore structure, while swelling and degradation tests evaluated the scaffold's stability. Compression testing determined mechanical strength, and in vitro cell culture assays assessed cell proliferation, osteogenic differentiation, and biomineralization. ResultsSEM results indicated that 3D scaffolds with probiotic bacterial HA had the desired 472 μm pore size. These scaffolds demonstrated a strain of 29.26 % and a compressive strength of 10 MPa, meeting the mechanical standards of human trabecular bone. Cell culture studies revealed enhanced cell proliferation by 50 %, osteogenic differentiation with 15.3 U/mg ALP activity, and 1.22-fold biomineralization, suggesting they are highly biocompatible and promote bone growth. ConclusionProbiotic bacterial HA scaffolds exhibit ideal properties and biocompatibility, enhancing bone regeneration and serving as an ideal alternative to chemical types.

Multiple myeloma: clinical characteristics, current therapies and emerging innovative treatments targeting ribosome biogenesis dynamics.

Multiple myeloma (MM) is a clinical disorder characterized by aberrant plasma cell growth in the bone marrow microenvironment. Globally, the prevalence of MM has been steadily increasing at an alarming rate. In the United States, more than 30,000 cases will be diagnosed in 2024 and it accounts for about 2% of cancer diagnoses and more than 2% of cancer deaths, more than double the worldwide figure. Both symptomatic and active MM are distinguished by uncontrolled plasma cell growth, which results in severe renal impairment, anemia, hypercalcemia, and bone loss. Multiple drugs have been approved by the FDA and are now widely used in clinical practice for MM. Although triplet and quadruplet induction regimens, autologous stem cell transplantation (ASCT), and maintenance treatment are used, MM continues to be an incurable illness characterized by relapses that may occur at various phases of its progression. MM patients with frailty, extramedullary disease, plasma cell leukemia, central nervous system recurrence, functional high risk, and the elderly are among those with the greatest current unmet needs. The high cost of care is an additional challenge. MM cells are highly protein secretary cells and thus are dependent on the activation of certain translation pathways. MM also has a high chance of altering ribosomal protein-encoding genes like MYC mutation. In this article we discuss the importance of ribosome biogenesis in promoting MM and RNA polymerase I inhibition as an upcoming treatment with potential promise for MM patients.

Four-mm-short implants in the rehabilitation of posterior atrophic jaws: A retrospective study on 212 patients with a mean follow-up of 8.02 years.

This study aimed to assess clinical efficacy of 4-mm-short implants in patients with posterior severe vertical bone atrophy in the medium- and long-term follow-up. Patients rehabilitated with 4-mm-short implants in the posterior atrophic jaws, with a minimum follow-up of 3 years post-loading, were included in the study. Data were collected for eligible patients, and marginal bone loss (MBL) for each implant was evaluated. The research outcomes were implant failure, MBL and complications. A total of 212 patients with 496 implants were included, resulting in a mean follow-up of 8.02 ± 2.17 years. The implant survival rate was 95.36% (95% CI: 93.12%-97.04%). More implant failures were observed in the maxilla (p = .02) and fewer failures were observed in patients undergoing more number of hygienic sessions per year (p < .001). The average MBL after 1-year-loading was 0.47 mm, increasing to 0.59 mm after 10 years; after 3 years no statistically significant increase in MBL was observed. Maxillary implants showed greater bone loss than mandibular ones (p < .001). More frequent professional oral hygiene sessions per year resulted being related with reduced MBL (p < .001). Four-mm-short implants showed high survival rates with an up to 10-year follow-up. Their use can offer a fixed prosthetic solution for patients with posterior vertical bone atrophy, minimizing surgical invasiveness, rehabilitative times and costs.

RECONSTRUCTION OF PAPROSKY TYPE III ACETABULAR BONE DEFECTS IN REVISION HIP ARTHROPLASTY USING A COMBINATION OF CAGE AND MORSELIZED ALLOGRAFTS

The management of severe acetabular bone defects poses a complex challenge in revision hip arthroplasty. Although biological fixation materials are currently dominant, cage has played an important role in complex acetabular revision in the past decades, especially when a biological prosthesis is not available. The purpose of this study is to report the long-term clinical and radiographic results of Paprosky type Ⅲ acetabular bone defects revised with cage and morselized allografts.We retrospectively analyzed 45 patients who underwent revision hip arthroplasty with cage and morselized allografts between January 2007 and January 2019. Forty-three patients were followed up. There were 19 Paprosky type IIIA bone defect patients and 24 Paprosky type IIIB bone defect patients and 7 patients of the 24 were also with pelvic discontinuity. Clinical assessment included Harris Hip Score (HHS) and Short Form-12 (SF-12). Radiographic assessment included cage stability, allografts incorporation, and center of rotation.All patients were followed up with a mean follow-up of 10.6 years, HHS and SF-12 improved significantly at last follow-up in comparison to the preoperative. There were 2 re-revisions, one at 5 years after surgery, another at 13.6 years after surgery. Two patients had nonprogressive radiolucency in zone III and the junction of zone II and zone III at the bone implant interface. Allografts of 40 (93%) cases incorporated fully.The combination of cage and morselized allograft is an alternative option for acetabular revision with Paprosky type III bone defects with satisfactory long-term follow-up results.

Alteration of bone microarchitecture in hereditary distal RTA patients with SLC4A1 gene mutation: assessed by HR-pQCT.

Hereditary distal renal tubular acidosis caused by SLC4A1 gene mutation (SLC4A1-dRTA) is a rare hereditary form of renal tubular acidosis. Rickets or osteomalacia is a common complication of SLC4A1-dRTA, and seriously affects patients' daily life. However, studies on the bone microstructure in SLC4A1-dRTA are limited. This work aimed to evaluate the bone microstructure of SLC4A1-dRTA patients, compared to age- and sex-matched healthy controls and X-linked hypophosphatemic rickets (XLH) patients. This was a retrospective study on eleven SLC4A1-dRTA patients. Clinical manifestations, biochemical and radiographical examinations were characterized. Bone microstructure was examined in seven SLC4A1-dRTA patients, seven healthy controls and twenty-one XLH patients using high-resolution peripheral quantitative computed tomography (HR-pQCT). Skeletal symptoms, including fracture, bone pain, and lower limb deformity, were presented in 72.7% of SLC4A1-dRTA patients. Short stature was presented in 63.6% of the patients. SLC4A1-dRTA patients had significantly lower volumetric BMD in the distal tibia, and more severe deteriorated trabecular bone in the distal radius and tibia than healthy controls. SLC4A1-dRTA patients had significantly more severe deteriorated trabecular bone in the distal radius and distal tibia compared to XLH patients. With long-term alkaline therapy, SLC4A1-dRTA patients had alleviation in bone pain, increase in height. Skeletal lesions were common clinical manifestations in SLC4A1-dRTA patients. Compared with XLH, another common type of rickets, SLC4A1-dRTA patients had more severe trabecular bone microstructure damage, further supporting the necessity of early diagnosis and timely treatment of the disease.

Deep Convolutional Neural Network for Automated Staging of Periodontal Bone Loss Severity on Bite-wing Radiographs: An Eigen-CAM Explainability Mapping Approach.

Periodontal disease is a significant global oral health problem. Radiographic staging is critical in determining periodontitis severity and treatment requirements. This study aims to automatically stage periodontal bone loss using a deep learning approach using bite-wing images. A total of 1752 bite-wing images were used for the study. Radiological examinations were classified into 4 groups. Healthy (normal), no bone loss; stage I (mild destruction), bone loss in the coronal third (< 15%); stage II (moderate destruction), bone loss is in the coronal third and from 15 to 33% (15-33%); stage III-IV (severe destruction), bone loss extending from the middle third to the apical third with furcation destruction (> 33%). All images were converted to 512 × 400 dimensions using bilinear interpolation. The data was divided into 80% training validation and 20% testing. The classification module of the YOLOv8 deep learning model was used for the artificial intelligence-based classification of the images. Based on four class results, it was trained using fivefold cross-validation after transfer learning and fine tuning. After the training, 20% of test data, which the system had never seen, were analyzed using the artificial intelligence weights obtained in each cross-validation. Training and test results were calculated with average accuracy, precision, recall, and F1-score performance metrics. Test images were analyzed with Eigen-CAM explainability heat maps. In the classification of bite-wing images as healthy, mild destruction, moderate destruction, and severe destruction, training performance results were 86.100% accuracy, 84.790% precision, 82.350% recall, and 84.411% F1-score, and test performance results were 83.446% accuracy, 81.742% precision, 80.883% recall, and 81.090% F1-score. The deep learning model gave successful results in staging periodontal bone loss in bite-wing images. Classification scores were relatively high for normal (no bone loss) and severe bone loss in bite-wing images, as they are more clearly visible than mild and moderate damage.

Osteoblastic Cell Sheet Engineering Using P(VCL-HEMA)-Based Thermosensitive Hydrogels Doped with pVCL@Icariin Nanoparticles Obtained with Supercritical CO2-SAS.

New clinical strategies for treating severe bone and cartilage injuries are required, especially for use in combination with implant procedures. For this purpose, p(VCL-co-HEMA) thermosensitive hydrogels have been activated with icariin-loaded nanoparticles to be used as bone-cell-harvesting platforms. Supercritical CO2-SAS technology has been applied to encapsulate icariin, a small molecule that is involved in osteoblastic differentiation. Thus, physical-chemical analysis, including swelling and transmittance, showed the impact of HEMA groups in hydrogel composition. Moreover, icariin (ICA) release from p(VCL-co-HEMA) platforms, including pVCL@ICA nanoparticles, has been studied to evaluate their efficacy in relevant conditions. Finally, the thermosensitive hydrogels' cell compatibility, transplant efficiency, and bone differentiation capacity were tested. This study identifies the optimal formulations for icariin-activated hydrogels for both control and HEMA formulations. Using this technique, osteoblastic sheets that were rich in collagen type I were successfully transplanted and recultivated, maintaining an optimal extracellular matrix (ECM) composition. These findings suggest a new cell-sheet-based therapy for bone regeneration purposes using customized and NP-activated pVCL-based cell platforms.

Fixed oil from the Caatinga palm Syagrus coronata with effect on Complete Freund's Adjuvant (CFA)-induced arthritis.

Syagrus coronata, a native palm tree in the Caatinga domain, produces fixed oil (ScFO) used therapeutically and dietary by Northeast Brazilian communities. This study evaluated its anti-inflammatory potential of CFA-induced arthritis and its effect on behavioral parameters. In the acute model, ScFO at 25, 50, and 100mg/kg showed edematogenic effects similar to indomethacin at 4mg/kg (p > 0.05). In the arthritis model, 100mg/kg ScFO treatment was comparable to indomethacin (4mg/kg) (p > 0.05). TNF-α and IL-1β levels were significantly reduced in ScFO-treated groups at 25, 50, and 100mg/kg, and the indomethacin group (4mg/kg) versus the positive control (p > 0.05). Radiographs showed severe soft-tissue swelling and bone deformities in the control group, while the 100mg/kg ScFO group had few alterations, similar to the indomethacin group. Histopathological analysis revealed intense lymphocytic infiltration in the control group, mild diffuse lymphocytic infiltration in the indomethacin group, and mild lymphoplasmacytic infiltration with focal polymorphonuclear infiltrates in the 100mg/kg ScFO group. Behavioral analysis showed improved exploratory stimuli in ScFO and indomethacin-treated mice compared to the positive control (p > 0.05). ScFO demonstrated anti-inflammatory effects in both acute and chronic arthritis models, reducing edema and pro-inflammatory cytokines, and improved exploratory behavior due to its analgesic properties.

Multi-omics analyses reveal aberrant differentiation trajectory with WNT1 loss-of-function in type XV osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a group of severe genetic bone disorders characterized by congenital low bone mass, deformity, and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 variants. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 variants and found that the proportion of type XV patients was around 10.3% (25 out of 243) with a diverse spectrum of phenotypes. Functional assays indicated that variants of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure, and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST (sclerostin) was dramatically reduced in type XV patients compared to patients with COL1A1 quantitative variants. Single-cell transcriptome data generated from human tibia samples of patients diagnosed with type XV OI and leg-length discrepancy, respectively, revealed aberrant differentiation trajectories of skeletal progenitors and impaired maturation of osteocytes with loss of WNT1, resulting in excessive CXCL12+ progenitors, fewer mature osteocytes, and the existence of abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV OI and relative low bone mass diseases such as early onset osteoporosis.

Cisplatin-induced bone marrow failure in an adult patient with Fanconi anemia.

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure typically developing in the first decade of life, congenital abnormalities, and an increased predisposition to malignancy. However, patients with FA can remain undiagnosed until adulthood and present with solid organ malignancies. Due to impaired DNA repair mechanisms, patients with FA are highly susceptible to severe bone marrow toxicity when treated with cisplatin. A 38-year-old woman, diagnosed with locally advanced squamous cell carcinoma (SCC) of the uterine cervix, underwent treatment with weekly cisplatin concurrent with radiotherapy. After the second week of cisplatin treatment, she presented with severe pancytopenia. The prolonged and severe pancytopenia following cisplatin and radiation, along with cervical SCC in the absence of risk factors and the presence of parental consanguinity, raised the possibility of FA as the underlying cause. Whole exome sequencing revealed a homozygous FANCI c.668A > C (p.Lys223Thr) missense variant confirming the diagnosis of FA. The pancytopenia exhibited a protracted course, necessitating admission and supportive treatment with antibiotics, red blood cell and platelet transfusions, as well as filgrastim and eltrombopag. Eventually, the pancytopenia improved after approximately 40 days of hospitalization. SCC of the head and neck or gynecologic organs in a young adult without known risk factors should prompt consideration of FA. Cisplatin should be avoided in patients with FA.

Delayed diagnosis of TAFRO syndrome: A case report.

TAFRO syndrome is a systemic inflammatory disorder, manifesting as thrombocytopenia (t), anasarca (a), fever (f), reticulin myelofibrosis/renal insufficiency (r), and organomegaly (o), and considered as a unique clinical subtype of idiopathic multicentric Castleman disease (iMCD). Such syndrome gave rise to a clinical picture similar to that of either a connective tissue disease or an autoimmune disease. A Chinese young female initially presenting with arthralgia, Raynaud phenomenon, generalized edema, and a positive anti-small nuclear ribonucleoprotein particle antibody was diagnosed as mixed connective tissue disease. The kidney biopsy showed thrombotic microangiopathy. Bone marrow smear showed bone marrow hyperplasia and biopsy revealed suspected light chain restricted expression, megakaryocyte proliferation, and moderate to severe bone marrow fibrosis. A lymph node biopsy was conducted and the histopathological findings were consistent with the subtype of mixed Castleman disease. The clinical symptoms were relieved after regular chemotherapy. After above examination results and clinical manifestations, the final diagnoses was TAFRO syndrome. The she was started on chemotherapy with bortezomib, cyclophosphamide, and dexamethasone. After chemotherapy, symptoms such as thrombocytopenia, hematuria and proteinuria disappeared, lymphadenopathy and VEGF level decreased, and bone marrow fibrosis relieved. Our case illustrated the first cases of shared characteristics of mixed connective tissue disease and iMCD-TAFRO syndrome. Cytokines may play a role in the shared pathogenicity of the iMCD-TAFRO syndrome and systemic autoimmune diseases. Therapy directly against inflammatory factors such as corticosteroids or chemotherapy have an important therapeutic implication.